The proximal objective of the project is to examine what role, if any, protein synthesis and CREB-mediated transcription play in the long-term stabilization of spatial representations in the hippocampus. These place representations are believed to be used by animals to solve spatial learning problems. Likewise, the long-term (but not short-term) stability of memory depends on protein synthesis and CREB-mediated transcription. First, the effect of cerebral protein synthesis inhibition on the stability of hippocampal place representations will be examined in mice according to a conventional technique. Second, two novel techniques for inducing CREB disruption have been developed and are both expected to produce deficits in long-term, but not short-term stability of the hippocampal spatial map. The specific aims of the proposal are to examine the effects on hippocampal place cell firing field stability of [1] protein synthesis inhibiton in wildtype mice, [2] inhibition of the cAMP/PKA pathway, via dopamine D1/D5 receptor blockade, in heterozygous CREBalphadelta+/- mice, and [3] the induction of a CREB repressor in transgenic mice. The ultimate objective is to test the hypothesis that spatial representations maintained by place cells mediate long-term spatial memory. This research will improve our understanding of the cellular mechanisms of hippocampus-dependent memory.